Objective To elucidate the causal relationship between serum metabolites and hepato-cellular carcinoma(HCC)by the Mendelian randomization.Methods The serum metabolite genome-wide association study(GWAS)data from the Metabolomics GWAS server was selected as the exposure group.The study sample includes 7 824 adults from two European population studies.The GWAS data of HCC was obtained from the IEU Open GWAS project as the outcome group,including a total sample of 197 611 cases,to evaluate the relationship between 486 serum metabolites and HCC.The inverse variance weighting method(IVW)was used as the primary analysis method.Supplementary analysis methods included MR-Egger,weighted median,simple mode,and weighted mode.Sensitivity analyses were conducted using Cochran's Q test,MR-Egger intercept test,leave-one-out analysis,and MR-PRESSO.Reverse MR and MR-Steiger tests were employed to exclude the influence of reverse causality.Metabolomic pathway analysis was performed using MetaboAnalyst 5.0.Results The MR results finally identified six metabolites with potential causal relationships with HCC:mannose(OR=0.38,95％CI:0.16-0.92,P=0.032),γ-glutamyltyrosine(OR=3.34,95％CI:1.14-9.83,P=0.028),glycerol-3-phosphate(OR=0.17,95％CI:0.04-0.70,P=0.014),2-linoleoylglycerophosphocholine(OR=0.33,95％CI:0.13-0.98,P=0.028),1-stearoylglycerophosphoethanolamine(OR=2.44,95％CI:1.05-5.65,P=0.038),and palmitoyl sphingomyelin(OR=5.62,95％CI:1.56-20.18,P=0.008).Sensitivity analyses for the six metabolites showed robustness,with no abnormal variables in the heterogeneity tests,and no evidence of genetic pleio-tropy was observed.Both reverse MR and Steiger tests did not support the existence of reverse causality between the metabolites and HCC.Metabolic pathway analysis indicated that ether lipid metabolism is closely related to the occurrence of HCC(P=0.002).Conclusion Six serum metabolites(mannose,γ-glutamyl-tyrosine,glycerol-3-phosphate,2-linoleoylglycerophosphocholine,1-stearoylglycerophosphoethanolamine,and palmitoyl sphingomyelin)have causal relationships with HCC.
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